Substituted azetidine dihydrothienopyridines and their use as phosphodiesterase inhibitors

ABSTRACT

The present invention relates to novel substituted azetidine dihydrothienopyridines with phosphodiesterase inhibitory activity, and to their use in therapy, and to pharmaceutical compositions comprising the compounds and to methods of treating diseases with the compounds (I)

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/772,615 filed Jun. 12, 2020, which is a national stage filing under35 U.S.C. § 371 of International Application No. PCT/EP2018/084978 filedDec. 14, 2018, which claims priority to European Patent Application No.17207661.4 filed Dec. 15, 2017. The contents of these applications areeach incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to novel substituted azetidinedihydrothienopyridines with phosphodiesterase inhibitory activity, andto their use in therapy, and to pharmaceutical compositions comprisingthe compounds and to methods of treating diseases with the compounds.

BACKGROUND OF THE INVENTION

Phosphodiesterases are enzymes that catalyse the hydrolysis of cyclicAMP and/or cyclic GMP in cells to 5-AMP and 5-GMP, respectively, and assuch they are critical to cellular regulation of cAMP or cGMP levels. Ofthe 11 phosphodiesterases identified so far, phosphodiesterase (PDE) 4,PDE7 and PDE8 are selective for cAMP. PDE4 is the most importantmodulator of cAMP expressed in immune and inflammatory cells such asneutrophils, macrophages and T-lymphocytes. As cAMP is a key secondmessenger in the modulation of inflammatory responses, PDE4 has beenfound to regulate inflammatory responses of inflammatory cells bymodulating proinflammatory cytokines such as TNF-α, IL-2, IFN-γ, GM-CSFand LTB4. Inhibition of PDE4 has therefore become an attractive targetfor the therapy of inflammatory diseases such as asthma, chronicobstructive pulmonary disease (COPD), rheumatoid arthritis, atopicdermatitis, psoriasis, inflammatory bowel disease such as Crohn'sdisease etc. (M. D. Houslay et al., Drug Discovery Today 10 (22), 2005,pp. 1503-1519). As atopic dermatitis (AD) patients have increasedPDE-activity, PDE4-inhibition would also appear to be a viable treatmentof AD (Journal of Investigative Dermatology (1986), 87(3), 372-6).

The PDE4 gene family consists at least of four genes, A, B, C and D,which have a high degree of homology (V. Boswell Smith and D. Spina,Curr. Opinion Investig. Drugs 6(11), 2006, pp. 1136-1141). The four PDE4isoforms are differentially expressed in different tissues and celltypes. Thus, PDE4B is predominantly expressed in monocytes andneutrophils, but not in cortex and epithelial cells, while PDE4D isexpressed in lung, cortex, cerebellum and T-cells (C. Kroegel and M.Foerster, Exp. Opinion Investig. Drugs 16(1), 2007, pp. 109-124).

Numerous PDE4 inhibitors have been studied for their therapeutic effecton inflammatory diseases, primarily asthma and COPD.

WO 2006/111549, US 20070259846, WO 2009/050236, WO 2009/050242, and WO2009/053268, (all Boehringer Ingelheim International) each disclosedihydrothieno-pyrimidines which are substituted with piperazine for thetreatment of respiratory or inflammatory diseases. The compounds arestated to inhibit the PDE4 enzyme.

WO 2007/118793, WO 2009/050248, and WO 2013/026797 (all BoehringerIngelheim International) each disclose dihydrothieno-pyrimidines whichare substituted with piperidine for the treatment of respiratory orinflammatory diseases. The compounds are stated to inhibit the PDE4enzyme.

WO 2014/066659, Tetra Discovery Partners, discloses bicyclic heteroarylcompounds which are stated to be inhibitors of PDE4.

There is a continuous need for developing novel PDE4 inhibitors whichhave a more favourable therapeutic window, i.e. fewer adverse effects,while retaining their therapeutic effect.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide novel substitutedazetidine dihydrothienopyridines. In one aspect the present inventionrelates to PDE4 inhibitors that could be useful as therapeutic agentsfor diseases mediated by PDE4, including dermal diseases or conditions,inflammatory allergic diseases, autoimmune diseases; acute or chroniccutaneous wound disorders, and the like.

The compounds of the present invention could have favourable oralbioavailability, solubility, absorption and metabolic stability. Theycould also have a favourable safety profile making them better toleratedthan other PDE4 inhibitors.

The compounds of the present invention could have low clearance in humanliver microsomes thus making them suitable for oral use.

The compounds of the present invention could have an improved windowover nausea and emesis side effect, relative to other PDE4 inhibitors,thus allowing them to be dosed at higher multiples of their PDE4potencies for greater therapeutic effect.

In one aspect the invention provides a compound of general formula (I)

whereinR¹ is selected from the group consisting of phenyl, 6 memberedheteroaryl, phenoxy and 6 membered heteroaryloxy; all of which areoptionally substituted with one or more substituents independentlyselected from R³; andR² is selected from the group consisting of (C₃-C₇)cycloalkyl, bridged(C₃-C₇)cycloalkyl and (4-7 membered) heterocycloalkyl; all of which areoptionally substituted with one or more substituents independentlyselected from R⁴; andR³ is selected from the group consisting of halogen, —CN, (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl and (C₃-C₆)cycloalkyl; andR⁴ is selected from the group consisting of fluoro, —CN, —OH,(C₁-C₄)alkyl, halo(C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl, —OR^(x),—S(O)₂R^(x), —S(O)₂NR^(a)R^(b), —C(O)R^(x), —C(O)(OR^(x)), and—C(O)NR^(a)R^(b); andR^(x) is selected from the group consisting of (C₁-C₄)alkyl and(C₃-C₆)cycloalkyl; andR^(a) and R^(b) are independently selected from the group consisting ofhydrogen, (C₁-C₄)alkyl and (C₃-C₆)cycloalkyl; andS* represents a chiral sulfur atom with (R) stereochemistry; andpharmaceutically acceptable salts, enantiomers, mixtures of enantiomers,diastereomers, mixtures of diastereomers, hydrates and solvates thereof.

In another aspect, the invention provides pharmaceutical compositionscomprising a compound of the invention as defined above together with apharmaceutically acceptable vehicle or excipient or pharmaceuticallyacceptable carrier(s), optionally together with one or more othertherapeutically active compound(s).

In another aspect, the invention provides the use of a compound of theinvention, for the manufacture of pharmaceutical compositions for theprophylaxis, treatment, prevention or amelioration of a disease,disorder or condition responsive to PDE4 inhibitory activity.

In yet another aspect the invention provides a method for treatment,prevention or alleviation of diseases, disorders or conditionsresponsive to PDE4 inhibitory activity, and which method comprises thestep of administering to a living animal body a therapeuticallyeffective amount of the compound of the invention.

Other objects of the invention will be apparent to the person skilled inthe art from the following detailed description and examples.

DETAILED DESCRIPTION OF THE INVENTION Definitions of the Invention

As used throughout the present specification and appended claims, thefollowing terms have the indicated meaning:

The term “alkyl” is intended to indicate a radical obtained when onehydrogen atom is removed from a branched or linear hydrocarbon. Saidalkyl comprises 1-6, such as 1-4, such as 1-3, such as 2-3 or such as1-2 carbon atoms. The term includes the subclasses normal alkyl(n-alkyl), secondary and tertiary alkyl, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl and isohexyl.

The terms “alkyloxy” and “alkoxy” are intended to indicate a radical ofthe formula —OR′, wherein R′ is alkyl as indicated herein, wherein thealkyl group is appended to the parent molecular moiety through an oxygenatom, e.g. methoxy (—OCH₃), ethoxy (—OCH₂CH₃), n-propoxy, isopropoxy,butoxy, tert-butoxy, and the like.

The term “hydroxyalkyl” is intended to indicate an alkyl group asdefined above substituted with one or more hydroxy, e.g. hydroxymethyl,hydroxyethyl, hydroxypropyl.

The term “halogen” is intended to indicate a substituent from the 7^(th)main group of the periodic table, such as fluoro, chloro and bromo,preferably fluoro.

The term “haloalkyl” is intended to indicate an alkyl group as definedherein substituted with one or more halogen atoms as defined herein,e.g. fluoro or chloro, such as fluoromethyl, difluoromethyl ortrifluoromethyl.

The terms “haloalkyloxy” and “haloalkoxy” are intended to indicate ahaloalkyl group as defined herein which is appended to the parentmolecular moiety through an oxygen atom, such as difluoromethoxy ortrifluoromethoxy.

The term “cycloalkyl” is intended to indicate a saturated cycloalkanehydrocarbon radical, as described herein. Said cycloalkyl comprises 3-7carbon atoms, such as 3-6 carbon atoms, such as 3-5 carbon atoms or suchas 3-4 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, or cycloheptyl.

The term “bridged cycloalkyl” is intended to indicate a saturatedcarbocyclic ring having the indicated number of carbon atoms andcontaining one or two carbon bridges. Representative examples include,but are not limited to, norbornyl, nortricyclyl, bicyclo[1.1.1]pentyl.

The term “heteroaryl” is intended to indicate radicals of monocyclicheteroaromatic rings comprising 5- or 6-membered ring which containsfrom 1-5 carbon atoms and from 1-4 heteroatoms selected from O, N, or S.The heteroaryl radical may be connected to the parent molecular moietythrough a carbon atom or a nitrogen atom contained anywhere within theheteroaryl group. Representative examples of (5-6) membered heteroarylgroups include, but are not limited to, furanyl, imidazolyl,isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiadiazolyl,thiazolyl, thienyl, triazolyl.

The term “6 membered heteroaryl” is intended to indicate radicals ofmonocyclic heteroaromatic rings, comprising a 6-membered ring, i.e.having a ring size of 6 atoms, which contain from 1-5 carbon atoms andfrom 1-5 heteroatoms, such as 1 heteroatom, such as 1-2 heteroatoms,such as 1-3 heteroatoms, such as 1-4 heteroatoms, where the heteroatomis N. Representative examples of 6 membered heteroaryl groups include,but are not limited to pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, andtriazinyl.

The term “heteroaryloxy” as used herein refers to the radicalheteroaryl-O—, where “heteroaryl” is as described above. Representativeexamples of 6 membered heteroaryloxy groups include, but are not limitedto pyrazinyloxy, pyridazinyloxy, pyridyloxy, pyrimidinyloxy,triazinyloxy.

The term “hydrocarbon radical” is intended to indicate a radicalcontaining only hydrogen and carbon atoms, it may contain one or moredouble and/or triple carbon-carbon bonds, and it may comprise cyclicmoieties in combination with branched or linear moieties. Saidhydrocarbon comprises 1-6 carbon atoms, and preferably comprises 1-5,e.g. 1-4, e.g. 1-3, e.g. 1-2 carbon atoms. The term includes alkyl,cycloalkyl and aryl, as indicated herein.

In some instances, the number of carbon atoms in a hydrocarbon radical(e.g. alkyl, cycloalkyl and aryl) is indicated by the prefix“(C_(a)-C_(b))”, wherein a is the minimum number and b is the maximumnumber of carbons in the hydrocarbon radical. Thus, for example(C₁-C₄)alkyl is intended to indicate an alkyl radical comprising from 1to 4 carbon atoms, and (C₃-C₆)cycloalkyl is intended to indicate acycloalkyl radical comprising from 3 to 6 carbon ring atoms.

The term “oxo” is intended to indicate an oxygen atom which is connectedto the parent molecular moiety via a double bond (═O).

The group “CN” is intended to represent cyano.

The group “OH” is intended to represent hydroxy.

The group “C(O)” is intended to represent a carbonyl group (C═O).

The group “S(O)₂” is intended to represent a sulfonyl group (S(═O)₂).

If substituents are described as being independently selected from agroup, each substituent is selected independent of the other. Eachsubstituent may therefore be identical or different from the othersubstituent(s).

The term “optionally substituted” means “unsubstituted or substituted”,and therefore the general formulas described herein encompassescompounds containing the specified optional substituent(s) as well ascompounds that do not contain the optional substituent(s).

The term “pharmaceutically acceptable salt” is intended to indicatesalts prepared by reacting a compound of formula I, which comprise abasic moiety, with a suitable inorganic or organic acid, such ashydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, phosphoric,formic, acetic, 2,2-dichloroacetic, adipic, ascorbic, L-aspartic,L-glutamic, galactaric, lactic, maleic, L-malic, phthalic, citric,propionic, benzoic, glutaric, gluconic, D-glucuronic, methanesulfonic,salicylic, succinic, malonic, tartaric, benzenesulfonic,ethane-1,2-disulfonic, 2-hydroxy ethanesulfonic acid, toluenesulfonic,sulfamic, fumaric and ethylenediaminetetraacetic acid. Pharmaceuticallyacceptable salts of compounds of formula I comprising an acidic moietymay also be prepared by reaction with a suitable base such as sodiumhydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide,silver hydroxide, ammonia or the like, or suitable non-toxic amines,such as lower alkylamines, hydroxy-lower alkylamines, cycloalkylamines,or benzylamines, or L-arginine or L-lysine. Further examples ofpharmaceutical acceptable salts are listed in Berge, S. M.; J. Pharm.Sci.; (1977), 66(1), 1-19, which is incorporated herein by reference.

The term “solvate” is intended to indicate a species formed byinteraction between a compound, e.g. a compound of formula I, and asolvent, e.g. alcohol, glycerol or water, wherein said species are in acrystalline form. When water is the solvent, said species is referred toas a hydrate.

The term “protic solvent” is intended to indicate a solvent which has anacidic hydrogen, such as water, or such as alcohols, e.g. methanol,ethanol or isopropanol.

The term “aprotic solvent” is intended to indicate a solvent which doesnot have an acidic hydrogen, such as for example dichloromethane,acetonitrile, dimethylformamide, dimethyl sulfoxide or acetone.

The term “treatment” as used herein means the management and care of apatient for the purpose of combating a disease, disorder or condition.The term is intended to include the delaying of the progression of thedisease, disorder or condition, the amelioration, alleviation or reliefof symptoms and complications, and/or the cure or elimination of thedisease, disorder or condition. The term may also include prevention ofthe condition, wherein prevention is to be understood as the managementand care of a patient for the purpose of combating the disease,condition or disorder and includes the administration of the activecompounds to prevent the onset of the symptoms or complications.Nonetheless, prophylactic (preventive) and therapeutic (curative)treatments are two separate aspects.

The terms “disease”, “condition” and “disorder” as used herein are usedinterchangeably to specify a state of a patient which is not the normalphysiological state of man.

The term “medicament” as used herein means a pharmaceutical compositionsuitable for administration of the pharmaceutically active compound to apatient.

The term “pharmaceutically acceptable” as used herein means suited fornormal pharmaceutical applications, i.e. giving rise to no adverseevents in patients etc.

EMBODIMENTS OF THE INVENTION

In one aspect the invention provides a compound of general formula (I)

whereinR¹ is selected from the group consisting of phenyl, 6 memberedheteroaryl, phenoxy and 6 membered heteroaryloxy; all of which areoptionally substituted with one or more substituents independentlyselected from R³; andR² is selected from the group consisting of (C₃-C₇)cycloalkyl, bridged(C₃-C₇)cycloalkyl and (4-7 membered) heterocycloalkyl; all of which areoptionally substituted with one or more substituents independentlyselected from R⁴; andR³ is selected from the group consisting of halogen, —CN, (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl and (C₃-C₆)cycloalkyl; andR⁴ is selected from the group consisting of fluoro, —CN, —OH,(C₁-C₄)alkyl, halo(C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl, —OR^(x),—S(O)₂R^(x), —S(O)₂NR^(a)R^(b), —C(O)R^(x), —C(O)(OR^(x)), and—C(O)NR^(a)R^(b); andR^(x) is selected from the group consisting of (C₁-C₄)alkyl and(C₃-C₆)cycloalkyl; andR^(a) and R^(b) are independently selected from the group consisting ofhydrogen, (C₁-C₄)alkyl and (C₃-C₆)cycloalkyl; andS* represents a chiral sulfur atom with (R) stereochemistry; andpharmaceutically acceptable salts, enantiomers, mixtures of enantiomers,diastereomers, mixtures of diastereomers, hydrates and solvates thereof.

In another embodiment of the present invention, R¹ is phenyl or phenoxy,optionally substituted with one of R³.

In another embodiment of the present invention, R³ is fluoro.

In another embodiment of the present invention, R² is piperidinyl,pyrrolidinyl or tetrahydropyranyl, all of which are optionallysubstituted with one or more substituents independently selected fromR⁴.

In another embodiment of the present invention, R² is piperidinyl orpyrrolidinyl, both of which are independently substituted with one of—C(O)R^(x) or —C(O)(OR^(x)), and R^(x) is methyl.

In another embodiment of the present invention, R² is tetrahydropyranyl.

In another embodiment the invention provides a compound selected fromthe following:

-   -   (1R)-5-(3-(4-Fluorophenyl)azetidin-1-yl)-7-((tetrahydro-2H-pyran-4-yl)amino)-2,3-dihydrothieno[3,2-b]pyridine        1-oxide;    -   Methyl        (3R)-3-[[(1R)-5-[3-(4-fluorophenyl)azetidin-1-yl]-1-oxido-2,3-dihydrothieno-[3,2-b]pyridin-7-yl]amino]piperidine-1-carboxylate;    -   Methyl        (3R)-3-[[(1R)-5-(3-(4-phenylazetidin-1-yl)-1-oxido-2,3-dihydrothieno[3,2-b]pyridin-7-yl]amino]piperidine-1-carboxylate;    -   (1R)-5-(3-(4-Fluorophenoxy)azetidin-1-yl)-7-((tetrahydro-2H-pyran-4-yl)amino)-2,3-dihydrothieno[3,2-b]pyridine-1-oxide;    -   Methyl        (3S)-3-[[(1R)-5-[3-(4-fluorophenoxy)azetidin-1-yl]-1-oxido-2,3-dihydrothieno[3,2-b]pyridine-7-yl]amino]pyrolidine-1-carboxylate;        1-[(3S)-3-[[(1R)-5-[3-(4-Fluorophenoxy)azetidin-1-yl]-1-oxido-2,3-dihydrothieno[3,2-b]pyridin-7-yl]amino]pyrrolidin-1-yl]ethenone;    -   (1R)-5-(3-Phenylazetidin-1-yl)-7-((tetrahydro-2H-pyran-4-yl)amino)-2,3-dihydrothieno[3,2-b]pyridine-1-oxide;        or a pharmaceutically acceptable salt, enantiomer, mixture of        enantiomers, diastereomer, mixture of diastereomers, hydrate and        solvate thereof.

The compounds of the invention may be obtained in crystalline formeither directly by concentration from an organic solvent or bycrystallisation or re-crystallisation from an organic solvent or mixtureof said solvent and a co-solvent that may be organic or inorganic, suchas water. The crystals may be isolated in essentially solvent-free formor as a solvate, such as a hydrate. The invention covers all crystallineforms, such as polymorphs and pseudopolymorphs, and also mixturesthereof.

The compounds of the invention may or may not comprise asymmetricallysubstituted (chiral) carbon atoms which give rise to the existence ofisomeric forms, e.g. enantiomers and possibly diastereomers. The presentinvention relates to all such isomers, either in optically pure form oras mixtures thereof (e.g. racemic mixtures or partially purified opticalmixtures). Pure stereoisomeric forms of the compounds and theintermediates of this invention may be obtained by the application ofprocedures known in the art. The various isomeric forms may be separatedby physical separation methods such as selective crystallization andchromatographic techniques, e.g. high pressure liquid chromatographyusing chiral stationary phases. Enantiomers may be separated from eachother by selective crystallization of their diastereomeric salts whichmay be formed with optically active amines or with optically activeacids.

Optically purified compounds may subsequently be liberated from saidpurified diastereomeric salts. Enantiomers may also be resolved by theformation of diastereomeric derivatives. Alternatively, enantiomers maybe separated by chromatographic techniques using chiral stationaryphases. Pure stereoisomeric forms may also be derived from thecorresponding pure stereoisomeric forms of the appropriate startingmaterials, provided that the reaction occur stereoselectively orstereospecifically. If a specific stereoisomer is desired, said compoundwill be synthesized by stereoselective or stereospecific methods ofpreparation. These methods will advantageously employ chiral purestarting materials.

Furthermore, when a double bond or a fully or partially saturated ringsystem is present in the molecule geometric isomers may be formed. It isintended that any geometric isomer, as separated, pure or partiallypurified geometric isomers or mixtures thereof are included within thescope of the invention.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. Isotopes of carbon include ¹³C and ¹⁴C.Isotopically-labelled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labelled reagent in place of the non-labelled reagentotherwise employed.

Medical Use

As the Compounds of the invention could exhibit PDE4 inhibitoryactivity, the Compounds could be useful as therapeutic agents forinflammatory allergic diseases such as bronchial asthma, COPD, allergicrhinitis, and nephritis; autoimmune diseases such as rheumatoidarthritis, multiple sclerosis, Crohn's disease ulcerative colitis,virtiligo, lupus, systemic lupus erythematosus, and discoid lupuserythematosus; acute or chronic cutaneous wound disorders; diseases ofthe central nervous system such as depression, amnesia, and dementia;organopathy associated with ischemic reflux caused by cardiac failure,shock, and cerebrovascular diseases, and the like; insulin-resistantdiabetes; wounds, and the like.

In one embodiment, the Compounds of the present invention are considereduseful for the treatment, prevention or alleviation of dermal diseasesor conditions.

In another embodiment, the Compounds of the present invention areconsidered useful for the treatment, prevention or alleviation of dermaldiseases or conditions selected from the group consisting ofproliferative and inflammatory skin disorders, dermatitis, atopicdermatitis, seborrheic dermatitis, contact dermatitis, includingirritative contact dermatitis and allergic contact dermatitis, handdermatitis, psoriasis, psoriasis vulgaris, inverse psoriasis, psoriaticarthritis, spondyloarthritis, epidermal inflammation, alopecia, alopeciaareata, rosacea, skin atrophy, steroid induced skin atrophy, photo skinageing, SAPHO syndrome, (synovitis, acne, pustulosis, hyperostosis andosteitis), acne vulgaris, hidradenitis suppurativa, urticaria, pruritis,and eczema.

In another embodiment, the Compounds of the present invention areconsidered useful for the treatment or alleviation of atopic dermatitis.

In another embodiment, the Compounds of the present invention areconsidered useful for the treatment or alleviation of psoriasis,psoriasis vulgaris, inverse psoriasis or psoriatic arthritis.

In another embodiment, the Compounds of the present invention areconsidered useful for the treatment or alleviation of psoriasis.

In another embodiment, the Compounds of the present invention areconsidered useful for the treatment or alleviation of alopecia areata.

In another embodiment, the Compounds of the present invention areconsidered useful for the treatment or alleviation of acne.

In another embodiment, the Compounds of the present invention areconsidered useful for the treatment or alleviation of pruritis.

In another embodiment, the Compounds of the present invention areconsidered useful for the treatment or alleviation of eczema.

Compounds of the invention, optionally in combination with other activecompounds, could be useful for the treatment of dermal diseases orconditions, in particular for the treatment of proliferative andinflammatory skin disorders, dermatitis, atopic dermatitis, seborrheicdermatitis, contact dermatitis, including irritative contact dermatitisand allergic contact dermatitis, hand dermatitis, psoriasis, psoriasisvulgaris, inverse psoriasis, psoriatic arthritis, spondyloarthritis,epidermal inflammation, alopecia, alopecia areata, rosacea, skinatrophy, steroid induced skin atrophy, photo skin ageing, SAPHOsyndrome, (synovitis, acne, pustulosis, hyperostosis and osteitis), acnevulgaris, hidradenitis suppurativa, urticaria, pruritis, and eczema.

Besides being useful for human treatment, the compounds of the presentinvention could also be useful for veterinary treatment of animalsincluding mammals such as horses, cattle, sheep, pigs, dogs, and cats.

Pharmaceutical Compositions of the Invention

For use in therapy, compounds of the present invention are typically inthe form of a pharmaceutical composition. The invention thereforerelates to a pharmaceutical composition comprising a compound of formula(I), optionally together with one or more other therapeutically activecompound(s), together with a pharmaceutically acceptable excipient orvehicle. The excipient must be “acceptable” in the sense of beingcompatible with the other ingredients of the composition and notdeleterious to the recipient thereof.

Conveniently, the active ingredient comprises from 0.0001-50% by weightof the formulation.

In the form of a dosage unit, the compound could be administered one ormore times a day at appropriate intervals, always depending, however, onthe condition of the patient, and in accordance with the prescriptionmade by the medical practitioner.

Conveniently, a dosage unit of a formulation contain between 0.001 mgand 1000 mg, preferably between 0.01 mg and 250 mg, such as 0.1-100 mgof a compound of formula (I).

A suitable dosage of the compound of the invention will depend, interalia, on the age and condition of the patient, the severity of thedisease to be treated and other factors well known to the practisingphysician. The compound could be administered either orally,parenterally or topically according to different dosing schedules, e.g.daily or with weekly intervals. In general a single dose will be in therange from 0.001 to 10 mg/kg body weight, e.g. in the range from 0.01 to5 mg/kg body weight. The compound could be administered as a bolus (i.e.the entire daily dose is administered at once) or in divided doses twoor more times a day.

In the context of topical treatment it could be more appropriate torefer to a “usage unit”, which denotes unitary, i.e. a single dose whichis capable of being administered to a patient, and which could bereadily handled and packed, remaining as a physically and chemicallystable unit dose comprising either the active material as such or amixture of it with solid or liquid pharmaceutical diluents or carriers.A “usage unit” is capable of being administered topically to a patientin an application per square centimetre of the skin of from 0.1 mg to 50mg and preferably from 0.2 mg to 5 mg of the final formulation inquestion

It is also envisaged that in certain treatment regimes, administrationwith longer intervals, e.g. every other day, every week, or even withlonger intervals could be beneficial.

If the treatment involves administration of another therapeuticallyactive compound it is recommended to consult Goodman & Gilman's ThePharmacological Basis of Therapeutics, 9^(th) Ed., J. G. Hardman and L.E. Limbird (Eds.), McGraw-Hill 1995, for useful dosages of saidcompounds.

The administration of a compound of the present invention with one ormore other active compounds could be either concomitantly orsequentially.

The formulations include e.g. those in a form suitable for oral(including sustained or timed release), rectal, parenteral (includingsubcutaneous, intraperitoneal, intramus-cular, intraarticular andintravenous), transdermal, ophthalmic, topical, dermal, nasal or buccaladministration.

The formulations may conveniently be presented in dosage unit form andmay be pre-pared by but not restricted to any of the methods well knownin the art of pharmacy, e.g. as disclosed in Remington, The Science andPractice of Pharmacy, 21ed ed., 2005. All methods include the step ofbringing the active ingredient into association with the carrier, whichconstitutes one or more accessory ingredients. In general, theformulations are prepared by uniformly and intimately bringing theactive ingredient into association with a liquid carrier, semisolidcarrier or a finely divided solid carrier or combinations of these, andthen, if necessary, shaping the product into the desired formulation.

For oral administration, including sustained or timed release, thecompound of formula (I) could typically be present in an amount of from0.001 to 20% by weight of the composition, such as 0.01% to about 10%.

Formulations of the present invention suitable for oral and buccaladministration could be in the form of discrete units as capsules,sachets, tablets, chewing gum or lozenges, each containing apredetermined amount of the active ingredient; in the form of a powder,granules or pellets; in the form of a solution or a suspension in anaqueous liquid or non-aqueous liquid, such as ethanol or glycerol; or inthe form of a gel, a nano- or microemulsion, an oil-in-water emulsion, awater-in-oil emulsion or other dispensing systems. The oils may beedible oils, such as but not restricted to e.g. cottonseed oil, sesameoil, coconut oil or peanut oil. Suitable dispersing or suspending agentsfor aqueous suspensions include synthetic or natural surfactants andviscosifying agents such as but not restricted to tragacanth, alginate,acacia, dextran, sodium carboxymethylcellulose, gelatin,methylcellulose, hydroxypropyl-methylcellulose, hydroxypropylcellulose,carbomers, polyvinylpyrrolidone, polysorbates, sorbitan fatty acidesters. The active ingredients could also be administered in the form ofa bolus, electuary or paste.

A tablet may be made by compressing, moulding or freeze drying theactive ingredient optionally with one or more accessory ingredients.Compressed tablets may be prepared by compressing, in a suitablemachine, the active ingredient(s) in a free-flowing form such as apowder or granules, optionally mixed by a binder and/or filler, such ase.g. lactose, glucose, mannitol starch, gelatine, acacia gum, tragacanthgum, sodium alginate, calcium phosphates, microcrystalline cellulose,carboxymethyl-cellulose, methylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, ethylcellulose, hydroxyethylcellulose,polyethylene glycol, waxes or the like; a lubricant such as e.g. sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride or the like; a disintegrating agent such ase.g. starch, methylcellulose, agar, bentonite, croscarmellose sodium,sodium starch glycollate, crospovidone or the like or a dispersingagent, such as polysorbate 80. Moulded tablets may be made by moulding,in a suitable machine, a mixture of the powdered active ingredient andsuitable carrier moistened with an inert liquid diluent. Freeze driedtablets may be formed in a freeze-dryer from a solution of the drugsubstance. A suitable filler can be included.

Formulations for rectal administration may be in the form ofsuppositories in which the compound of the present invention is admixedwith low melting point, water soluble or insoluble solids such as cocoabutter, hydrogenated vegetable oils, polyethylene glycol or fatty acidsesters of polyethylene glycols, while elixirs may be prepared usingmyristyl palmitate.

Formulations suitable for parenteral administration convenientlycomprise a sterile oily or aqueous preparation of the activeingredients, which is preferably isotonic with the blood of therecipient, e.g. isotonic saline, isotonic glucose solution or buffersolution. Furthermore, the formulation may contain co-solvent,solubilising agent and/or complexation agents. The formulation may beconveniently sterilised by for instance filtration through a bacteriaretaining filter, addition of sterilising agent to the formulation,irradiation of the formulation or heating of the formulation. Liposomalformulations as disclosed in e.g. Encyclopedia of PharmaceuticalTechnology, vol. 9, 1994, are also suitable for parenteraladministration.

Alternatively, the compounds of formula (I) could be presented as asterile, solid preparation, e.g. a freeze-dried powder, which is readilydissolved in a sterile solvent immediately prior to use.

Transdermal formulations may be in the form of a plaster, patch,microneedles, liposomal or nanoparticulate delivery systems or othercutaneous formulations applied to the skin.

Formulations suitable for ophthalmic administration may be in the formof a sterile aqueous preparation of the active ingredients, which may bein micro-crystalline form, for example, in the form of an aqueousmicrocrystalline suspension. Liposomal formulations or biodegradablepolymer systems e.g. as disclosed in Encyclopedia of PharmaceuticalTechnology, vol. 2, 1989, may also be used to present the activeingredient for ophthalmic administration.

Formulations suitable for topical, such as dermal, intradermal orophthalmic administration include liquid or semi-solid preparations suchas liniments, lotions, gels, applicants, sprays, foams, film formingsystems, microneedles, micro- or nano-emulsions, oil-in-water orwater-in-oil emulsions such as creams, ointments or pastes; or solutionsor suspensions such as drops. Compositions for ophthalmic treatment mayadditionally contain cyclodextrin.

For topical administration, the compound of formula (I) could typicallybe present in an amount of from 0.001 to 20% by weight of thecomposition, such as 0.01% to about 10%, but could also be present in anamount of up to about 100% of the composition.

Formulations suitable for nasal or buccal administration include powder,self-propelling and spray formulations, such as aerosols and atomisers.Such formulations are disclosed in greater detail in e.g. ModernPharmaceutics, 2^(nd) ed., G. S. Banker and C. T. Rhodes (Eds.), page427-432, Marcel Dekker, New York; Modern Pharmaceutics, 3^(th) ed., G.S. Banker and C. T. Rhodes (Eds.), page 618-619 and 718-721, MarcelDekker, New York and Encyclopedia of Pharmaceutical Technology, vol. 10,J. Swarbrick and J. C. Boylan (Eds), page 191-221, Marcel Dekker, NewYork.

In addition to the aforementioned ingredients, the formulations of acompound of formula (I) may include one or more additional ingredientssuch as diluents, buffers, flavouring agents, colourant, surface activeagents, thickeners, penetration enhancing agents, solubility enhancingagents preservatives, e.g. methyl hydroxybenzoate (includinganti-oxidants), emulsifying agents and the like.

When the active ingredient is administered in the form of salts withpharmaceutically acceptable non-toxic acids or bases, preferred saltsare for instance easily water-soluble or slightly soluble in water, inorder to obtain a particular and appropriate rate of absorption.

The pharmaceutical composition may additionally comprise one or moreother active components conventionally used in the treatment of dermaldisease or conditions, e.g. selected from the group consisting ofglucocorticoids, vitamin D and vitamin D analogues, antihistamines,platelet activating factor (PAF) antagonists, anticholinergic agents,methylxanthines, β-adrenergic agents, COX-2 inhibitors, JAK inhibitors,other PDE inhibitors, salicylates, indomethacin, flufenamate, naproxen,timegadine, gold salts, penicillamine, serum cholesterol loweringagents, retinoids, zinc salts, salicylazosulfapyridine and calcineurininhibitors.

Methods of Preparation

The compounds of the present invention can be prepared in a number ofways well known to those skilled in the art of synthesis. The compoundsof the invention could for example be prepared using the reactions andtechniques outlined below together with methods known in the art ofsynthetic organic chemistry, or variations thereof as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below. The reactions are carried out in solventsappropriate to the reagents and materials employed and suitable for thetransformations being effected. Also, in the synthetic methods describedbelow, it is to be understood that all proposed reaction conditions,including choice of solvent, reaction atmosphere, reaction temperature,duration of experiment and work-up procedures, are chosen to beconditions of standard for that reaction, which should be readilyrecognized by one skilled in the art. Not all compounds falling into agiven class may be compatible with some of the reaction conditionsrequired in some of the methods described. Such restrictions to thesubstituents which are compatible with the reaction conditions will bereadily apparent to one skilled in the art and alternative methods canbe used.

The compounds of the present invention or any intermediate could bepurified, if required, using standard methods well known to a syntheticorganist chemist, e.g. methods described in “Purification of LaboratoryChemicals”, 6^(th) ed. 2009, W. Amarego and C. Chai,Butterworth-Heinemann.

Starting materials are either known or commercially available compounds,or may be prepared by routine synthetic methods well known to a personskilled in the art. Unless otherwise noted, reagents and solvents wereused as received from commercial suppliers. Proton nuclear magneticresonance spectra were obtained on a Bruker AVANCE 400 spectrometer at400 MHz, and Bruker AVANCE 500 spectrometer at 500 MHz.Tetramethylsilane was used as an internal standard for proton spectra.The value of a multiplet, either defined doublet (d), triplet (t),quartet (q) or (m) at the approximate midpoint is given unless a rangeis quoted. (br) indicates a broad peak, whilst (s) indicates a singlet.Thin layer chromatography was performed using Merck 6OF254 silica-gelTLC plates. Visualisation of TLC plates was performed using UV light(254 nm). Mass spectra were obtained on a Shimadzu LCMS-2010EVspectrometer using electrospray ionization (ESI) and/oratmospheric-pressure chemical ionization (APCI).

The following abbreviations have been used throughout:

ABPR automated back pressure regulatorBINAP 2,2′bis(diphenylphosphino)-1,1′-binaphthyldba dibenzylideneacetoneDCM dichloromethaneDMSO dimethylsulfoxideEtOAc ethyl acetateEtOH ethanolHPLC high-performance liquid chromatographKO^(t)Bu potassium tert-butoxideLCMS liquid chromatography-mass spectrometryMe methylMeCN acetontitrileMeOH methanolMHz megahertzMTBE methyl tert-butyl etherNaOMe sodium methoxideNMR nuclear magnetic resonanceppm parts per millionSFC supercritical fluid chromatographyTLC thin layer chromatography

General Methods

Compounds of the invention may be prepared according to the followingnon-limiting general methods and examples:

5,7-Dichloro-2,3-dihydrothieno[3,2-b]pyridine can be prepared, as shownin Scheme 1, by the methods described in Preparations 1 to 5.

Compounds of general formula (Int1) can be prepared, as shown in Scheme2, by reaction of 5,7-dichloro-2,3-dihydrothieno[3,2-b]pyridine(Preparation 5) with amines of general formula (Int4), which are eithercommercially available or can readily be synthesised by methods known tothose skilled in the art.

Typical reaction conditions involve reacting a solution of5,7-dichloro-2,3-dihydrothieno[3,2-b]pyridine (Preparation 5) in asuitable solvent, or solvent mixture, such as 1,4-dioxane, with an amineof formula (Int4) in the presence of a palladium catalyst and aninorganic or organic base, such as potassium ^(t)butoxide, potassiumcarbonate or caesium carbonate. A suitable palladium catalyst isPd₂(dba)₃ in the presence of BINAP and a suitable base is potassium^(t)butoxide, as exemplified in Preparation 6.

Sulfoxides of general formula (Int2) can be prepared, as shown in Scheme2, by reaction of compounds of general formula (Int1) with a suitableoxidising agent in an appropriate solvent, optionally in the presence ofa chiral catalyst. For example, a solution of compounds of generalformula (Int1) in EtOH/water can be oxidised by treatment with NaIO₄, ata temperature between 0° C. and room temperature as outlined inPreparation 9. Sulfoxides of general formula (Int2) can be prepared assingle enantiomers or, alternatively, as mixtures of enantiomers whichare then separated by methods know to those skilled in the art.Alternatively it may be preferable to take compounds forward as mixturesof enantiomers and separate the enantiomers at a later stage, asdescribed in Example 1.

Compounds of general formula (I) can be prepared, as shown in Scheme 2,by reaction of compounds of general formula (Int2) with amines ofgeneral formula R¹NH₂, which are commercially available or can readilybe synthesised by methods known to those skilled in the art. Typicalreaction conditions involve reacting a solution of a compound of generalformula (Int2) in a suitable solvent, or solvent mixture, such as1,4-dioxane, with an amine of formula R¹NH₂ in the presence of apalladium catalyst and an inorganic or organic base, such as potassium^(t)butoxide, potassium carbonate or caesium carbonate. A suitablepalladium catalyst is palladium acetate in the presence of BINAP and asuitable base is caesium carbonate, as exemplified in Example 1. Thecompounds of general formula (I) may initially be synthesised asmixtures of enantiomers, which are then separated by methods know tothose skilled in the art.

Alternatively, compounds of general formula (Int3) can be prepared, asshown in Scheme 2, by reaction of compounds of general formula (Int1)with amines of general formula R¹NH₂, which are commercially availableor can readily be synthesised by methods known to those skilled in theart. Typical reaction conditions involve reacting a solution of acompound of general formula (Int1) in a suitable solvent, or solventmixture, such as 1,4-dioxane, with an amine of formula R¹NH₂ in thepresence of a palladium catalyst and an inorganic or organic base, suchas potassium ^(t)butoxide, potassium carbonate or caesium carbonate. Asuitable palladium catalyst is Pd₂(dba)₃ in the presence of BINAP and asuitable base is potassium ^(t)butoxide, as exemplified in Preparation12.

Compounds of general formula (I) can then be prepared, as shown inScheme 2, by reaction of compounds of general formula (Int3) with asuitable oxidising agent in an appropriate solvent, optionally in thepresence of a chiral catalyst. For example, a solution of compounds ofgeneral formula (Int3) in EtOH/water can be oxidised by treatment withNaIO₄, at a temperature between 0° C. and room temperature as outlinedin Example 7.

The sulfoxide of formula (Int5) can be prepared, as shown in Scheme 3,by reaction of 5,7-dichloro-2,3-dihydrothieno[3,2-b]pyridine(Preparation 5) with a suitable oxidising agent in an appropriatesolvent, optionally in the presence of a chiral catalyst. For example, asolution of 5,7-dichloro-2,3-dihydrothieno[3,2-b]pyridine (Preparation5) in EtOH/water can be oxidised by treatment with NaIO₄, at atemperature between 0° C. and room temperature.

Compounds of general formula (Int2) can be prepared, as shown in Scheme3, by reaction of the sulfoxide (Int5) with amines of general formula(Int4), which are either commercially available or can readily besynthesised by methods known to those skilled in the art. Typicalreaction conditions involve reacting the sulfoxide (Int5) and theappropriate amine of formula (Int3) in a suitable protic, or polaraprotic, solvent at a temperature between room temperature and theboiling point of the solvent, in the presence of an added organic orinorganic base.

Alternatively, a compound of general formula (Int2) can be prepared fromthe sulfoxide (Int5) by reaction with an amine of general formula (Int4)in a suitable solvent, or solvent mixture, such as 1,4-dioxane, in thepresence of a palladium catalyst and a suitable inorganic or organicbase, such as potassium ^(t)butoxide, potassium carbonate or caesiumcarbonate.

PREPARATIONS AND EXAMPLES Preparation 1 Methyl3-amino-4,5-dihydrothiophene-2-carboxylate

Acrylonitrile (76.2 mL, 1.13 mol) was added to a stirred solution ofNaOMe (61.0 g, 1.13 mol) and methyl 2-sulfanylacetate (86 mL, 0.943 mol)in MeOH (600 mL) at 0° C. The reaction mixture was stirred for 2 days atroom temperature. The reaction mass was cooled to 0° C. and quenchedwith aq. citric acid solution (1000 mL). The reaction mass was thenextracted with EtOAc and the organic layer was washed with water. Theresultant organic layer was dried over Na₂SO₄ and concentrated underreduced pressure to give the crude product. MTBE was added to the crudeproduct and the resultant solid was filtered to afford the titlecompound as a solid. ¹H NMR (CDCl₃, 500 MHz): δ (ppm) 7.12-7.04 (m, 2H),3.57 (s, 3H), 2.98-2.88 (m, 2H), 2.85-2.76 (m, 2H); LCMS (ESI): m/z 160[M+H]+; 99%; RT=1.40 min; (AQUITY UPLC BEH C18 column, 0.1% FORMIC ACIDin water with MeCN).

Preparation 2 Methyl3-(3-methoxy-3-oxopropanamido)-4,5-dihydrothiophene-2-carboxylate

KHCO₃ (118.6 g, 1.18 mol) was added to a stirred solution of thecompound of Preparation 1 (42.0 g, 264.2 mmol) in DCM (500 mL) at 0° C.After stirring for 5 minutes a solution of methyl malonyl chloride (42.6mL, 396.2 mmol) in DCM (150 mL) was added slowly to it at 0° C. Thereaction mixture was stirred for 2 hours at room temperature. Aftercompletion of the reaction the solids were filtered off and the filtratewas concentrated under vacuum to afford the crude product. MTBE (65 mL)was added to the crude mass and the resultant suspension was filtered toafford the title compound as a solid. The compound was used in the nextstep without further purification. ¹H NMR (CDCl₃, 400 MHz): δ (ppm)11.08-10.98 (m, 1H), 3.81 (d, 3=6.6 Hz, 6H), 3.63 (t, 3=8.6 Hz, 2H),3.44 (s, 2H), 3.18 (t, 3=8.7 Hz, 2H); LCMS (ESI): m/z 260 [M+H]+; 97%;RT=1.85 min; (AQUITY UPLC BEH C18 column, 0.1% FORMIC ACID in water withMeCN).

Preparation 3 Methyl7-chloro-5-oxo-2,3,4,5-tetrahydrothieno[3,2-b]pyridine-6-carboxylate

A solution of the compound of Preparation 2 (42.0 g, 174 mmol) and 30%NaOMe in MeOH (193 mL, 1.04 mol) was stirred at 70° C. for 1 hour. Afterconsumption of all starting material (by TLC) the reaction mass wascooled to 0° C. and an aq. solution of citric acid was added to it togive a pH of approximately 4. The resulting precipitate was filtered andwashed with cold water to afford the pure title compound as a solid. ¹HNMR (DMSO-d6, 400 MHz): δ (ppm) 13.20-13.14 (m, 1H), 12.08-11.98 (m,1H), 3.80 (s, 3H), 3.36-3.32 (m, 2H), 3.19-3.08 (m, 2H); LCMS (ESI): m/z228 [M+H]+; 99%; RT=1.29 min; (AQUITY UPLC BEH C18 column, 0.1% FORMICACID in water with MeCN).

Preparation 4 2,3-Dihydrothieno[3,2-b]pyridine-5,7-diol

A mixture of the compound of Preparation 3 (2.20 g, 9.69 mmol) and 2MNaOH (46 mL, 92 mmol) was heated at reflux for 3 hours. The reactionmixture was cooled to 0° C. and an aq. solution of citric acid was addedto it to achieve a pH of approximately 7. The resulting precipitate wasfiltered, washed with cold water and dried under reduced pressure toafford the title compound. ¹H NMR (DMSO-d6, 500 MHz): δ (ppm)11.33-11.00 (m, 1H), 11.52-10.81 (m, 1H), 5.48-5.38 (m, 1H), 3.25-3.20(m, 2H), 3.09-2.95 (m, 2H); LCMS (ESI): m/z 170 [M+H]+; 98%; RT=1.42min; (AQUITY UPLC BEH C18 column, 0.1% FORMIC ACID in water with MeCN).

Preparation 5 5,7-Dichloro-2,3-dihydrothieno[3,2-b]pyridine

N,N-dimethyl aniline (10.1 mL, 79.8 mmol) was added slowly at 0° C. to astirred solution of the compound of Preparation 4 (3.0 g, 17.8 mmol) inPOCl₃ (6.76 mL, 72.8 mmol) and the reaction mixture was stirred at 155°C. in sealed tube for 16 hours. The reaction mixture was then cooled toroom temperature and poured into ice cold water. The mixture wasextracted with EtOAc (2×100 mL) and the combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude product was purified by silica gel (100-200mesh) column chromatography (5-15% EtOAc in pet ether as eluent) toafford the title compound as a solid. ¹H NMR (CDCl₃, 400 MHz): δ (ppm)7.12 (s, 1H), 3.67-3.17 (m, 4H); LCMS (ESI): m/z 206 [M+H]+; 88%;RT=2.10 min; (AQUITY UPLC BEH C18 column, 0.1% FORMIC ACID in water withMeCN).

Preparation 67-Chloro-5-(3-(4-fluorophenyl)azetidin-1-yl)-2,3-dihydrothieno[3,2-b]pyridine

KO^(t)Bu (3.90 g, 35.0 mmol) was added to a stirred solution of thecompound of Preparation 5 (2.4 g, 11.7 mmol) and3-(4-fluorophenyl)azetidine (2.19 g, 11.7 mmol) in 1,4-dioxane (23 mL).After stirring for 5 min, Pd₂(dba)₃ (1.06 g, 1.16 mmol) and BINAP (720mg, 1.16 mmol) were added. The reaction mixture was heated for 2 hoursat 70° C. then cooled to room temperature and filtered through a celitepad, washing with EtOAc. The filtrate was concentrated under reducedpressure to give the crude product which was subjected to flashchromatography using 20% EtOAc in hexane as eluent to afford the puretitle compound as a solid. ¹H NMR (DMSO-d6, 400 MHz): δ (ppm) 7.52-7.38(m, 2H), 7.25-7.14 (m, 2H), 6.38 (s, 1H), 4.31 (t, 3=8.0 Hz, 2H),3.99-3.90 (m, 1H), 3.89-3.82 (m, 2H), 3.38-3.34 (m, 2H), 3.29-3.22 (m,2H); LCMS (ESI): m/Z 320[M+H]+; 99%; RT=2.01 min; (AQUITY UPLC BEH C18column, 0.1% FORMIC ACID in water with MeCN).

Preparation 77-Chloro-5-(3-phenylazetidin-1-yl)-2,3-dihydrothieno[3,2-b]pyridine

The title compound was prepared using the same method as Preparation 6,starting from the compound of Preparation 5 and 3-phenylazetidine. Theproduct was obtained as a solid. ¹H NMR (DMSO-d6, 400 MHz): δ (ppm)7.38-7.28 (m, 4H), 7.28-7.18 (m, 1H), 6.38 (s, 1H), 4.32 (t, 3=7.9 Hz,2H), 3.97-3.90 (m, 1H), 3.90-3.86 (m, 2H), 3.38-3.33 (m, 2H), 3.29-3.22(m, 2H); LCMS (ESI): m/z 303 [M+H]+; 92%; RT=2.73 min; (AQUITY UPLC BEHC18 column, 0.1% FORMIC ACID in water with MeCN).

Preparation 87-Chloro-5-(3-(4-fluorophenoxy)azetidin-1-yl)-2,3-dihydrothieno[3,2-b]pyridine

The title compound was prepared using the same method as Preparation 6,starting from the compound of Preparation 5 and3-(4-fluorophenoxy)azetidine. The product was obtained as a solid. ¹HNMR (CDCl₃, 400 MHz): δ (ppm) 7.05-6.94 (m, 2H), 6.79-6.60 (m, 2H), 6.14(s, 1H), 5.12-4.97 (m, 1H), 4.42-4.25 (m, 2H), 4.09-3.91 (m, 2H),3.36-3.32 (m, 2H), 3.26-3.23 (m, 2H); LCMS (ESI): m/z 337 [M+H]+; 93%;RT=2.43 min; (AQUITY UPLC BEH C18 column, 0.1% FORMIC ACID in water withMeCN).

Preparation 97-Chloro-5-(3-(4-fluorophenyl)azetidin-1-yl)-2,3-dihydrothieno[3,2-b]pyridine-1-oxide

NaIO₄ (2.1 g, 9.96 mmol) was added to a stirred solution of the compoundof Preparation 6 (2.9 g, 9.06 mmol) in EtOH/H₂O (6.0 mL, 1:1 ratio) andthe reaction was stirred at room temperature for 16 h. After completionof the reaction (monitored by TLC) the reaction mass was diluted withEtOAc and the organic layer was separated, dried over Na₂SO₄ andconcentrated under reduced pressure to afford the title compound as asolid which was used without further purification. LCMS (ESI): m/z 337[M+H]+; 76%; RT=2.01 min; (AQUITY UPLC BEH C18 column, 0.1% FA in waterwith MeCN).

Preparation 107-Chloro-5-(3-phenylazetidin-1-yl)-2,3-dihydrothieno[3,2-b]pyridine-1-oxide

According to the method of Preparation 9, the compound of Preparation 7was reacted to give the title compound as a solid. LCMS (ESI): m/z 319[M+1]+; 93%; RT=1.90 min; (AQUITY UPLC BEH C18 column, 0.1% FA in waterwith MeCN).

Preparation 117-Chloro-5-(3-(4-fluorobenzyl)azetidin-1-yl)-2,3-dihydrothieno[3,2-b]pyridine-1-oxide

According to the method of Preparation 9, the compound of Preparation 8was reacted to give the title compound as a solid. ¹H NMR (CDCl₃, 400MHz): δ (ppm) 7.09-6.86 (m, 2H), 6.79-6.58 (m, 2H), 6.20 (s, 1H),5.15-5.01 (m, 1H), 4.55-4.36 (m, 2H), 4.22-4.11 (m, 2H), 3.96-3.76 (m,1H), 3.36-3.07 (m, 3H) LCMS (ESI): m/z 353 [M+H]⁺; 98%; RT=1.75 min;(AQUITY UPLC BEH C18 column, 0.1% FORMIC ACID in water with MeCN).

Preparation 125-(3-Phenylazetidin-1-yl)-N-(tetrahydro-2H-pyran-4-yl)-2,3-dihydrothieno[3,2-b]pyridin-7-amine

The title compound was prepared, as a solid, according to the method ofExample 1 using the compound of Preparation 7 andtetrahydropyran-4-amine. LCMS (ESI): m/z 368 [M+H]⁺; 83%; RT=1.93 min;(AQUITY UPLC BEH C18 column, 0.1% FA in water with MeCN).

Example 1(1R)-5-(3-(4-Fluorophenyl)azetidin-1-yl)-7-((tetrahydro-2H-pyran-4-yl)amino)-2,3-dihydrothieno[3,2-b]pyridine1-oxide

Cs₂CO₃ (8.1 g, 25.0 mmol) and BINAP (518 mg, 0.83 mmol) were added to astirred solution of the compound of Preparation 9 (2.8 g, 8.33 mmol) andtetrahydropyran-4-amine (1.2 g, 12.5 mmol) in 1,4-dioxane (30 mL),followed by palladium acetate (186 mg, 0.83 mmol). The reaction mixturewas heated for 16 hours at 100° C. The reaction mixture was cooled toroom temperature and filtered through a celite pad, washing with EtOAc.The filtrate was concentrated under reduced pressure to afford the crudeproduct. Purification by flash chromatography using 3% MeOH/DCM aseluent gave the racemic product (1.6 g, 50%). Further purification wasthen carried out by chiral SFC using a (R,R) WHELK-01 column andmethanol as co-solvent. The solvent was removed in vacuo to afford thetitle compound as a solid. ¹H NMR (DMSO-d6, 500 MHz): δ (ppm) 7.44-7.36(m, 2H), 7.18 (t, 3=8.9 Hz, 2H), 6.40 (d, 3=8.2 Hz, 1H), 5.44 (s, 1H),4.40-4.32 (m, 2H), 3.98-3.81 (m, 5H), 3.73-3.63 (m, 1H), 3.52-3.35 (m,3H), 3.27-3.21 (m, 1H), 3.05-2.95 (m, 1H), 2.93-2.86 (m, 1H), 1.92-1.85(m, 2H), 1.64-1.51 (m, 2H); LCMS (ESI): m/z 402 [M+H]⁺; 99%; RT=1.64min; (AQUITY UPLC BEH C18 column, 0.1% FORMIC ACID in water with MeCN)and Chiral HPLC ˜99% SFC METHOD: Injection volume: 14 μl, Co-Solvent:Methanol, Column: (R,R) WHELK-01(4.6*250) mm, 5 u, Temperature: 30° C.,Flow: 4, Pressure: 100, RT: 5.39 min.

Example 2 Methyl(3R)-3-[[(1R)-5-[3-(4-fluorophenyl)azetidin-1-yl]-1-oxido-2,3-dihydrothieno-[3,2-b]pyridin-7-yl]amino]piperidine-1-carboxylate

The title compound was prepared in the same manner as the compound ofExample 1 using the compound of Preparation 9 and methyl(3R)-3-aminopiperidine-1-carboxylate. Final purification was by chiralSFC using a Chiralpak AD-H column and methanol as co-solvent. Thesolvent was removed in vacuo to afford the title compound as a solid. ¹HNMR (DMSO-d6, 500 MHz): δ (ppm) 7.46-7.35 (m, 2H), 7.23-7.13 (m, 2H),6.45-6.35 (m, 1H), 5.55-5.43 (m, 1H), 4.41-4.32 (m, 2H), 4.12-3.80 (m,5H), 3.58 (s, 3H), 3.50-3.41 (m, 2H), 3.30-3.25 (m, 1H), 3.08-2.95 (m,1H), 3.01-2.85 (m, 1H), 2.83-2.63 (m, 2H), 2.05-1.88 (m, 1H), 1.71-1.56(m, 2H), 1.54-1.43 (m, 1H); LCMS (ESI): m/z 459 [M+H]⁺; 99%; RT=1.40min; (AQUITY UPLC BEH C18 column, 0.1% FORMIC ACID in water with MeCN)and Chiral HPLC ˜99% SFC METHOD: Column: Chiralpak AD-H (4.6*250) mm, 5u, Co-solvent: 0.5% DEA in Methanol, Total flow: 4 g/mn, % Co-solvent:40%, Temperature: 30° C., ABPR: 100 bar, RT: 2.16 min.

Example 3 Methyl(3R)-3-[[(1R)-5-(3-(4-phenylazetidin-1-yl)-1-oxido-2,3-dihydrothieno[3,2-b]pyridin-7-yl]amino]piperidine-1-carboxylate

The title compound was prepared in the same manner as the compound ofExample 1 using the compound of Preparation 10 and methyl(3R)-3-aminopiperidine-1-carboxylate. Final purification was by chiralSFC using a Chiralpak AD-H column and methanol as co-solvent. Thesolvent was removed in vacuo to afford the title compound as a solid. ¹HNMR (DMSO-d6, 500 MHz): δ (ppm) 7.40-7.33 (m, 4H), 7.30-7.22 (m, 1H),6.45-6.37 (m, 1H), 5.55-5.43 (m, 1H), 4.43-4.33 (m, 2H), 4.09-3.80 (m,5H), 3.58 (s, 3H), 3.51-3.42 (m, 2H), 3.31-3.24 (m, 1H), 3.06-2.95 (m,1H), 3.05-2.95 (m, 1H), 2.85-2.62 (m, 2H), 2.01-1.90 (m, 1H), 1.72-1.58(m, 2H), 1.53-1.44 (m, 1H); LCMS (ESI): m/z 441 [M+H]⁺; 99%; RT=1.39min; (AQUITY UPLC BEH C18 column, 0.1% FORMIC ACID in water with MeCN)and Chiral HPLC ˜98% SFC METHOD: Column: CHIRALCEL OD-H (4.6*250) mm 5u, Co-solvent: 0.5% DEA in Methanol, Total flow: 4 g/mn, % Co-solvent:40%, Temperature: 30° C., ABPR: 100 bar, RT: 4.47 min.

Example 4(1R)-5-(3-(4-Fluorophenoxy)azetidin-1-yl)-7-((tetrahydro-2H-pyran-4-yl)amino)-2,3-dihydrothieno[3,2-b]pyridine-1-oxide

The title compound was prepared in the same manner as the compound ofExample 1 using the compound of Preparation 11 andtetrahydropyran-4-amine. Final purification was by chiral SFC using aChiralpak IC column and methanol as co-solvent. The solvent was removedin vacuo to afford the title compound as a solid. ¹H NMR (DMSO-d6, 500MHz): δ (ppm) 7.19-7.05 (m, 2H), 6.94-6.84 (m, 2H), 6.39 (d, 3=8.2 Hz,1H), 5.46 (s, 1H), 5.16-5.06 (m, 1H), 4.49-4.38 (m, 2H), 3.96-3.80 (m,4H), 3.73-3.62 (m, 1H), 3.49-3.37 (m, 3H), 3.28-3.23 (m, 1H), 3.05-2.94(m, 1H), 2.92-2.86 (m, 1H), 1.85-1.74 (m, 2H), 1.63-1.51 (m, 2H); LCMS(ESI): m/z 418 [M+H]⁺; 99%; RT=1.64 min; (AQUITY UPLC BEH C18 column,0.1% FORMIC ACID in water with MeCN) and Chiral HPLC ˜99% SFC METHOD:Column: Chiralpak AS-H (4.6*250) mm 5 u, Co-solvent: 0.5% DEA inMethanol, Total flow: 4 g/mn, % Co-solvent: 40%, Temperature: 30° C.,Outlet Pressure: 100 bar, RT: 2.18 min.

Example 5 Methyl(3S)-3-[[(1R)-5-[3-(4-fluorophenoxy)azetidin-1-yl]-1-oxido-2,3-dihydrothieno[3,2-b]pyridine-7-yl]amino]pyrrolidine-1-carboxylate

The title compound was prepared in the same manner as the compound ofExample 1 using the compound of Preparation 11 and methyl(3S)-3-aminopyrrolidine-1-carboxylate. Final purification was by chiralSFC using a Chiralpak AD-H column and methanol as co-solvent. Thesolvent was removed in vacuo to afford the title compound as a solid. ¹HNMR (DMSO-d6, 500 MHz): δ (ppm) 7.17-7.10 (m, 2H), 6.95-6.87 (m, 2H),6.90-6.80 (m, 1H), 5.44 (s, 1H), 5.17-5.05 (m, 1H), 4.48-4.38 (m, 2H),4.25-4.15 (m, 1H), 3.89 (td, 3=3.2, 9.3 Hz, 2H), 3.65-3.58 (m, 2H),3.62-3.54 (m, 2H), 3.53-3.40 (m, 2H), 3.37-3.34 (m, 1H), 3.27-3.20 (m,2H), 3.05-2.95 (m, 1H), 2.93-2.86 (m, 1H), 2.30-2.08 (m, 1H), 2.01-1.89(m, 1H); LCMS (ESI): m/z 461 [M+H]⁺; 96%; RT=1.70 min; (AQUITY UPLC BEHC18 column, 0.1% FORMIC ACID in water with MeCN) and Chiral HPLC ˜99%SFC METHOD: Column: Chiralpak AS-H (4.6*250) mm 5 u, Co-solvent: 0.5%DEA in Methanol, Total flow: 3 g/mn, % Co-solvent: 40%, Back pressure:1002, RT: 4.02 min.

Example 61-[(3S)-3-[[(1R)-5-[3-(4-Fluorophenoxy)azetidin-1-yl]-1-oxido-2,3-dihydrothieno[3,2-b]pyridin-7-yl]amino]pyrrolidin-1-yl]ethanone

The title compound was prepared in the same manner as the compound ofExample 1 using the compound of Preparation 11 and1-[(3S)-3-aminopyrrolidin-1-yl]ethanone. Final purification was bychiral SFC using a Chiralpak AD-H column and methanol as co-solvent. Thesolvent was removed in vacuo to afford the title compound. ¹H NMR(DMSO-d6, 500 MHz): δ (ppm) 7.14-7.04 (m, 2H), 6.93-6.86 (m, 2H),6.40-6.32 (m, 1H), 5.50-5.42 (m, 1H), 5.15-5.06 (m, 1H), 4.50-4.39 (m,2H), 4.33-4.19 (m, 1H), 3.98-3.89 (m, 2H), 3.86-3.63 (m, 1H), 3.61-3.41(m, 3H), 3.40-3.21 (m, 3H), 2.90-2.86 (m, 1H), 2.26-2.10 (m, 1H),2.08-1.84 (m, 4H); LCMS (ESI): m/z 445 [M+H]⁺; 99%; RT=1.60 min; (AQUITYUPLC BEH C18 column, 0.1% FORMIC ACID in water with MeCN) and ChiralHPLC ˜99% SFC METHOD: Column: Chiralpak AS-H (4.6*250) mm 5 u,Co-solvent: 0.5% DEA in Methanol, Total flow: 4 g/mn, % Co-solvent: 40%,Temperature: 30° C., Outlet Pressure: 100 bar, RT: 3.72 min.

Example 7(1R)-5-(3-Phenylazetidin-1-yl)-7-((tetrahydro-2H-pyran-4-yl)amino)-2,3-dihydrothieno[3,2-b]pyridine-1-oxide

According to the method of Preparation 9 the compound of Preparation 12was reacted with NaIO₄ to give racemic title compound. Finalpurification was by chiral SFC using a Chiralcel OJ-H column andmethanol as co-solvent. The solvent was removed in vacuo to afford thetitle compound as a solid. ¹H NMR (DMSO-d6, 500 MHz): δ (ppm) 7.38-7.32(m, 4H), 7.29-7.25 (m, 1H), 6.48-6.38 (m, 1H), 5.45 (s, 1H), 4.41-4.33(m, 2H), 3.96-3.91 (m, 3H), 3.90-3.83 (m, 2H), 3.72-3.63 (m, 1H),3.50-3.35 (m, 3H), 3.28-3.22 (m, 1H), 3.03-2.94 (m, 1H), 2.93-2.86 (m,1H), 1.90-1.78 (m, 2H), 1.63-1.51 (m, 2H); LCMS (ESI): m/z 384 [M+H]⁺;97%; RT=1.60 min; (AQUITY UPLC BEH C18 column, 0.1% FORMIC ACID in waterwith MeCN) and Chiral HPLC ˜97% SFC METHOD: Column: CHIRALCEL OJ-H(4.6*250) mm 5 u, Co-solvent: 0.5% DEA in Methanol, Total flow: 4 g/mn,%Co-solvent: 40%, Temperature: 30° C., ABPR: 100 bar, RT: 2.07 min.

PDE4 Assay

The human PDE4D catalytic domain (UniProt no. Q08499 [S380-L740]) wasincubated with a mixture of non-labelled cAMP (cyclic adenosinemonophosphate) and fluorescein amidite (FAM) conjugated cAMP andtitrated test or reference compound. Following brief incubation theenzymatic reaction was stopped by addition of binding buffer containingnanoparticles with immobilized trivalent metal ions capable ofbinding 1) AMP phospho groups and 2) terbium (Tb) donor fluorophores.Subsequent excitation of the Tb donor triggers time-resolved FRET toadjacent FAM acceptor molecules resulting in light emission. In thepresence of a PDE4 inhibitor, AMP generation was reduced resulting in alower fluorescence signal. The cAMP phosphodiester is not bound by thedetection system.

The results were calculated as the molar concentrations resulting in 50%inhibition of the substrate cleavage compared to controls samples, andare expressed as IC₅₀ (nM).

PDE4 IC₅₀ ranges:* indicates that IC₅₀ values are >50 nM and <150 nM** indicates that IC₅₀ values are >10 and <50 nM*** indicates that IC₅₀ values are <10 nM

TNF-α Release

Human peripheral blood mononuclear cells (PBMC) were isolated from buffycoats. The blood is mixed with saline at a ratio of 1:1, and the PBMCwere isolated using Lymphoprep tubes™ (Nycomed, Norway). The PBMC weresuspended in RPMI1640 with 0.5% human serum albumin, pen/strep and 2 mML-glutamine at a concentration of 5×105 c/ml. The cells werepre-incubated for 30 minutes with the test compounds in 96 well tissueculture plates and stimulated for 18 hours with lipopolysaccharide 1mg/ml (Sigma). TNF-α concentration in the supernatants was measuredusing homogeneous time-resolved fluorescence resonance (TR-FRET). Theassay is quantified by measuring fluorescence at 665 nm (proportional toTNF-α concentration) and 620 nm (control).

Results were expressed as IC₅₀ values calculated from inhibition curvesusing as positive controls the secretion in LPS stimulated wells and asnegative controls the secretion in unstimulated cells.

TNF-α IC₅₀ Ranges:

* indicates that IC₅₀ values are >50 nM and <150 nM** indicates that IC₅₀ values are >10 and <50 nM*** indicates that IC₅₀ values are <10 nM

The results are shown in Table 1 below.

TABLE 1 PDE4 TNF-α Example IC₅₀ range IC₅₀ range 1 ** *** 2 *** *** 3*** *** 4 ** ** 5 * * 6 *** ** 7 ** **

CLAUSES

In view of the description the present inventors have in particularprovided: Clause 1. A compound of general formula (I)

whereinR¹ is selected from the group consisting of phenyl, 6 memberedheteroaryl, phenoxy and 6 membered heteroaryloxy; all of which areoptionally substituted with one or more substituents independentlyselected from R³; andR² is selected from the group consisting of (C₃-C₇)cycloalkyl, bridged(C₃-C₇)cycloalkyl and (4-7 membered) heterocycloalkyl; all of which areoptionally substituted with one or more substituents independentlyselected from R⁴; andR³ is selected from the group consisting of halogen, —CN, (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl and (C₃-C₆)cycloalkyl; andR⁴ is selected from the group consisting of fluoro, —CN, —OH,(C₁-C₄)alkyl, halo(C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl, —OR^(x),—S(O)₂R^(x), —S(O)₂NR^(a)R^(b), —C(O)R^(x), —C(O)(OR^(x)), and—C(O)NR^(a)R^(b); andR^(x) is selected from the group consisting of (C₁-C₄)alkyl and(C₃-C₆)cycloalkyl; andR^(a) and R^(b) are independently selected from the group consisting ofhydrogen, (C₁-C₄)alkyl and (C₃-C₆)cycloalkyl; andS* represents a chiral sulfur atom with (R) stereochemistry; orpharmaceutically acceptable salts, enantiomers, mixtures of enantiomers,diastereomers, mixtures of diastereomers, hydrates and solvates thereof.Clause 2. A compound according to clause 1, wherein R¹ is phenyl.Clause 3. A compound according to clause 1, wherein R¹ is phenylsubstituted with one of R³.Clause 4. A compound according to clause 3, wherein R³ is halogen.Clause 5. A compound according to clause 3 or 4, wherein R¹ is phenylsubstituted with fluoro.Clause 6. A compound according to clause 1, wherein R¹ 6 memberedheteroaryl.Clause 7. A compound according to clause 1, wherein R¹ is phenoxysubstituted with one of R³.Clause 8 A compound according to clause 7, wherein R¹ is phenoxysubstituted with fluoro.Clause 9. A compound according to clause 1, wherein R¹ is 6 memberedheteroaryloxy.Clause 10. A compound according to any one of the clauses 1-9, whereinR² is (C₃-C₇)cycloalkyl or bridged (C₃-C₇)cycloalkyl, optionallysubstituted with one or more substituents independently selected fromR⁴.Clause 11. A compound according to any one of the clauses 1-9, whereinR² is (4-7) membered heterocycloalkyl, optionally substituted with oneor more substituents independently selected from R⁴.Clause 12. A compound according to clause 11, wherein R² is (5-6)membered heterocycloalkyl, optionally substituted with one of R⁴.Clause 13. A compound according to clause 12, wherein R² is piperidinyl,pyrrolidinyl or tetrahydropyranyl, all of which are optionallysubstituted with —C(O)R^(x), or —C(O)(OR^(x)), and R^(x) is(C₁-C₄)alkyl.Clause 14. A compound according to clause 13, wherein R² is piperidinylor pyrrolidinyl, both of which are independently substituted with one of—C(O)R^(x) or —C(O)(OR^(x)), and R^(x) is methyl.Clause 15. A compound according to clause 13, wherein R² istetrahydropyranyl.Clause 16. A compound according to any one of the clauses 1-15, whereinR¹ is phenyl which is optionally substituted with halogen; and R² is(5-6 membered) heterocycloalkyl, which is optionally substituted withone of C(O)R^(x), or —C(O)(OR^(x)), and R^(x) is methyl R⁴; orpharmaceutically acceptable salts, enantiomers, mixtures of enantiomers,diastereomers, mixtures of diastereomers, hydrates and solvates thereof.Clause 17. A compound according to clause 16, wherein R¹ is phenyl; andR² is (5-6 membered) heterocycloalkyl, which is optionally substitutedwith one of C(O)R^(x), or —C(O)(OR^(x)), and R^(x) is methyl R⁴; orpharmaceutically acceptable salts, enantiomers, mixtures of enantiomers,diastereomers, mixtures of diastereomers, hydrates and solvates thereof.Clause 18. A compound according to clause 17, wherein R¹ is phenyl; andR² is piperidinyl, pyrrolidinyl or tetrahydropyranyl, all of which areoptionally substituted with one of C(O)R^(x), or —C(O)(OR^(x)), andR^(x) is methyl R⁴; or pharmaceutically acceptable salts, enantiomers,mixtures of enantiomers, diastereomers, mixtures of diastereomers,hydrates and solvates thereof.Clause 19. A compound according to clause 16, wherein R¹ is phenylsubstituted with fluoro; and R² is (5-6 membered) heterocycloalkyl; orpharmaceutically acceptable salts, enantiomers, mixtures of enantiomers,diastereomers, mixtures of diastereomers, hydrates and solvates thereof.Clause 20. A compound according to clause 19, wherein R¹ is phenylsubstituted with fluoro; and R² is piperidinyl or pyrrolidinyl, both ofwhich are independently substituted with one of —C(O)R^(x) or—C(O)(OR^(x)), and R^(x) is methyl; or pharmaceutically acceptablesalts, enantiomers, mixtures of enantiomers, diastereomers, mixtures ofdiastereomers, hydrates and solvates thereof.Clause 21. A compound according to clause 19, wherein R¹ is phenylsubstituted with fluoro; and R² is tetrahydropyranyl; orpharmaceutically acceptable salts, enantiomers, mixtures of enantiomers,diastereomers, mixtures of diastereomers, hydrates and solvates thereof.Clause 22. A compound according to any one of the clauses 1-15, whereinR¹ is phenoxy which is optionally substituted with halogen; and R² is(5-6 membered) heterocycloalkyl, which is optionally substituted withone of C(O)R^(x), or —C(O)(OR^(x)), and R^(x) is methyl R⁴; orpharmaceutically acceptable salts, enantiomers, mixtures of enantiomers,diastereomers, mixtures of diastereomers, hydrates and solvates thereof.Clause 23. A compound according to clause 22, wherein R¹ is phenoxy; andR² is (5-6 membered) heterocycloalkyl, which is optionally substitutedwith one of C(O)R^(x), or —C(O)(OR^(x)), and R^(x) is methyl R⁴; orpharmaceutically acceptable salts, enantiomers, mixtures of enantiomers,diastereomers, mixtures of diastereomers, hydrates and solvates thereof.Clause 24. A compound according to clause 22, wherein R¹ is phenyoxysubstituted with fluoro; and R² is piperidinyl, pyrrolidinyl ortetrahydropyranyl, all of which are optionally substituted with one ofC(O)R^(x), or —C(O)(OR^(x)), and R^(x) is methyl R⁴; orpharmaceutically acceptable salts, enantiomers, mixtures of enantiomers,diastereomers, mixtures of diastereomers, hydrates and solvates thereof.Clause 25. A compound according to any one of the preceding clausesselected from the group consisting of

-   -   (1R)-5-(3-(4-Fluorophenyl)azetidin-1-yl)-7-((tetrahydro-2H-pyran-4-yl)amino)-2,3-dihydrothieno[3,2-b]pyridine        1-oxide;    -   Methyl        (3R)-3-[[(1R)-5-[3-(4-fluorophenyl)azetidin-1-yl]-1-oxido-2,3-dihydrothieno-[3,2-b]pyridin-7-yl]amino]piperidine-1-carboxylate;    -   Methyl        (3R)-3-[[(1R)-5-(3-(4-phenylazetidin-1-yl)-1-oxido-2,3-dihydrothieno[3,2-b]pyridin-7-yl]amino]piperidine-1-carboxylate;    -   (1R)-5-(3-(4-Fluorophenoxy)azetidin-1-yl)-7-((tetrahydro-2H-pyran-4-yl)amino)-2,3-dihydrothieno[3,2-b]pyridine-1-oxide;    -   Methyl        (3S)-3-[[(1R)-5-[3-(4-fluorophenoxy)azetidin-1-yl]-1-oxido-2,3-dihydrothieno[3,2-b]pyridine-7-yl]amino]pyrolidine-1-carboxylate;    -   1-[(3S)-3-[[(1R)-5-[3-(4-Fluorophenoxy)azetidin-1-yl]-1-oxido-2,3-dihydrothieno[3,2-b]pyridin-7-yl]amino]pyrrolidin-1-yl]ethenone;    -   (1R)-5-(3-Phenylazetidin-1-yl)-7-((tetrahydro-2H-pyran-4-yl)amino)-2,3-dihydrothieno[3,2-b]pyridine-1-oxide;        or a pharmaceutically acceptable salt, enantiomer, mixture of        enantiomers, diastereomer, mixture of diastereomers, hydrate and        solvate thereof.        Clause 26. A compound which is    -   (1R)-5-(3-(4-Fluorophenyl)azetidin-1-yl)-7-((tetrahydro-2H-pyran-4-yl)amino)-2,3-dihydrothieno[3,2-b]pyridine        1-oxide.        Clause 27. A compound which is    -   Methyl        (3R)-3-[[(1R)-5-[3-(4-fluorophenyl)azetidin-1-yl]-1-oxido-2,3-dihydrothieno-[3,2-b]pyridin-7-yl]amino]piperidine-1-carboxylate.        Clause 28. A compound which is    -   Methyl        (3R)-3-[[(1R)-5-(3-(4-phenylazetidin-1-yl)-1-oxido-2,3-dihydrothieno[3,2-b]pyridin-7-yl]amino]piperidine-1-carboxylate.        Clause 29. A compound which is    -   (1R)-5-(3-(4-Fluorophenoxy)azetidin-1-yl)-7-((tetrahydro-2H-pyran-4-yl)amino)-2,3-dihydrothieno[3,2-b]pyridine-1-oxide.        Clause 30. A compound which is    -   Methyl        (3S)-3-[[(1R)-5-[3-(4-fluorophenoxy)azetidin-1-yl]-1-oxido-2,3-dihydrothieno[3,2-b]pyridine-7-yl]amino]pyrolidine-1-carboxylate.        Clause 31. A compound which is    -   1-[(3S)-3-[[(1R)-5-[3-(4-Fluorophenoxy)azetidin-1-yl]-1-oxido-2,3-dihydrothieno[3,2-b]pyridin-7-yl]amino]pyrrolidin-1-yl]ethenone.        Clause 32. A compound which is    -   (1R)-5-(3-Phenylazetidin-1-yl)-7-((tetrahydro-2H-pyran-4-yl)amino)-2,3-dihydrothieno[3,2-b]pyridine-1-oxide.        Clause 33. A pharmaceutical composition comprising a compound        according to any one of clauses 1-32 together with a        pharmaceutically acceptable vehicle or excipient or        pharmaceutically acceptable carrier(s).        Clause 34. The pharmaceutical composition according to clause 33        further comprising one or more other therapeutically active        compound(s).        Clause 35. A use of the compound according to any of the clauses        1-32, for the manufacture of a pharmaceutical composition.        Clause 36. The use of a compound according to clause 35 in the        manufacture of a pharmaceutical composition for the treatment or        amelioration of a disease, disorder or condition responsive to        PDE4 inhibitory activity.        Clause 37 The use according to clause 36, wherein the disease,        disorder or condition is dermal diseases, disorders or        conditions.        Clause 38. The use according to clause 37, wherein the dermal        disease, disorder or condition is proliferative and inflammatory        skin disorders, dermatitis, atopic dermatitis, seborrheic        dermatitis, contact dermatitis, including irritative contact        dermatitis and allergic contact dermatitis, hand dermatitis,        psoriasis, psoriasis vulgaris, inverse psoriasis, psoriatic        arthritis, spondyloarthritis, epidermal inflammation, alopecia,        alopecia areata, rosacea, skin atrophy, steroid induced skin        atrophy, photo skin ageing, SAPHO syndrome, (synovitis, acne,        pustulosis, hyperostosis and osteitis), acne vulgaris,        hidradenitis suppurativa, urticaria, pruritis, and eczema.        Clause 39. The use according to clause 38, wherein the dermal        disease, disorder or condition is inflammatory skin disorders.        Clause 40. The use according to clause 38, wherein the dermal        disease, disorder or condition is dermatitis, atopic dermatitis,        seborrheic dermatitis, contact dermatitis, including irritative        contact dermatitis and allergic contact dermatitis or hand        dermatitis.        Clause 41. The use according to clause 57, wherein the dermal        disease, disorder or condition is atopic dermatitis.        Clause 42. The use according to clause 55, wherein the dermal        disease, disorder or condition is psoriasis, psoriasis vulgaris,        inverse psoriasis or psoriatic arthritis.        Clause 43. The use according to clause 59, wherein the dermal        disease, disorder or condition is psoriasis.        Clause 44. The compound according to any of the clauses 1-32,        for use as a medicament.        Clause 45. The compound according to any of the clauses 1-32 for        use in the treatment or amelioration of a disease, disorder or        condition responsive to PDE4 inhibitory activity.        Clause 46. The compound according to any of the clauses 1-32 for        use in the treatment or amelioration of dermal diseases,        disorders or conditions.

Clause 47. The compound according to any of the clauses 1-32 for use inthe treatment or amelioration of proliferative and inflammatory skindisorders, dermatitis, atopic dermatitis, seborrheic dermatitis, contactdermatitis, including irritative contact dermatitis and allergic contactdermatitis, hand dermatitis, psoriasis, psoriasis vulgaris, inversepsoriasis, psoriatic arthritis, spondyloarthritis, epidermalinflammation, alopecia, alopecia areata, rosacea, skin atrophy, steroidinduced skin atrophy, photo skin ageing, SAPHO syndrome, (synovitis,acne, pustulosis, hyperostosis and osteitis), acne vulgaris,hidradenitis suppurativa, urticaria, pruritis, and eczema.

Clause 48. The compound according to any of the clauses 1-32 for use inthe treatment or amelioration of inflammatory skin disorders.Clause 49. The compound according to any of the clauses 1-32 for use inthe treatment or amelioration of dermatitis, atopic dermatitis,seborrheic dermatitis, contact dermatitis, including irritative contactdermatitis and allergic contact dermatitis or hand dermatitis.Clause 50. The compound according to any of the clauses 1-32 for use inthe treatment or amelioration of atopic dermatitis.Clause 51. The compound according to any of the clauses 1-32 for use inthe treatment or amelioration of psoriasis, psoriasis vulgaris, inversepsoriasis or psoriatic arthritis.Clause 52. The compound according to any of the clauses 1-32 for use inthe treatment or amelioration of psoriasis.Clause 53. The compound according to any of the clauses 1-32 forsystemic treatment of a disease, disorder or condition responsive toPDE4 inhibitory activity.Clause 54. The compound according to any of the clauses 1-32 forsystemic treatment of dermal diseases, disorders or conditions.Clause 55. The compound according to any of the clauses 1-32 forsystemic treatment of proliferative and inflammatory skin disorders,dermatitis, atopic dermatitis, seborrheic dermatitis, contactdermatitis, including irritative contact dermatitis and allergic contactdermatitis, hand dermatitis, psoriasis, psoriasis vulgaris, inversepsoriasis, psoriatic arthritis, spondyloarthritis, epidermalinflammation, alopecia, alopecia areata, rosacea, skin atrophy, steroidinduced skin atrophy, photo skin ageing, SAPHO syndrome, (synovitis,acne, pustulosis, hyperostosis and osteitis), acne vulgaris,hidradenitis suppurativa, urticaria, pruritis, and eczema.Clause 56. The compound according to any of the clauses 1-32 forsystemic treatment of inflammatory skin disorders.Clause 57. The compound according to any of the clauses 1-32 forsystemic treatment of dermatitis, atopic dermatitis, seborrheicdermatitis, contact dermatitis, including irritative contact dermatitisand allergic contact dermatitis or hand dermatitis.Clause 58. The compound according to any of the clauses 1-32 forsystemic treatment of atopic dermatitis.Clause 59. The compound according to any of the clauses 1-32 forsystemic treatment of psoriasis, psoriasis vulgaris, inverse psoriasisor psoriatic arthritis.Clause 60. The compound according to any of the clauses 1-32 forsystemic treatment of psoriasis.Clause 61. The compound according to any of the clauses 1-32 for oraltreatment of a disease, disorder or condition responsive to PDE4inhibitory activity.Clause 62. The compound according to any of the clauses 1-32 for oraltreatment of dermal diseases, disorders or conditions.Clause 63. The compound according to any of the clauses 1-32 for oraltreatment of proliferative and inflammatory skin disorders, dermatitis,atopic dermatitis, seborrheic dermatitis, contact dermatitis, includingirritative contact dermatitis and allergic contact dermatitis, handdermatitis, psoriasis, psoriasis vulgaris, inverse psoriasis, psoriaticarthritis, spondyloarthritis, epidermal inflammation, alopecia, alopeciaareata, rosacea, skin atrophy, steroid induced skin atrophy, photo skinageing, SAPHO syndrome, (synovitis, acne, pustulosis, hyperostosis andosteitis), acne vulgaris, hidradenitis suppurativa, urticaria, pruritis,and eczema.Clause 64. The compound according to any of the clauses 1-32 for oraltreatment of inflammatory skin disorders.Clause 65. The compound according to any of the clauses 1-32 for oraltreatment of dermatitis, atopic dermatitis, seborrheic dermatitis,contact dermatitis, including irritative contact dermatitis and allergiccontact dermatitis or hand dermatitis.Clause 66. The compound according to any of the clauses 1-32 for oraltreatment of atopic dermatitis.Clause 67. The compound according to any of the clauses 1-32 for oraltreatment of psoriasis, psoriasis vulgaris, inverse psoriasis orpsoriatic arthritis.Clause 68. The compound according to any of the clauses 1-32 for oraltreatment of psoriasis.Clause 69. A method for treatment or alleviation of a disease or adisorder or a condition responsive to PDE4 inhibitory activity, whichmethod comprises the step of administering to a living animal body atherapeutically effective amount of a compound according to any of theclauses 1-32.Clause 70. A method of treating or ameliorating dermal diseases,disorders or conditions, the method comprising administering to a personsuffering from at least one of said diseases an effective amount of oneor more compounds according to according to any one of clauses 1-32,optionally together with a pharmaceutically acceptable carrier or one ormore excipients, optionally in combination with other therapeuticallyactive compounds.Clause 71. The method according to clause 70, wherein the dermaldisease, disorder or condition is selected from the group consisting ofproliferative and inflammatory skin disorders, dermatitis, atopicdermatitis, seborrheic dermatitis, contact dermatitis, includingirritative contact dermatitis and allergic contact dermatitis, handdermatitis, psoriasis, psoriasis vulgaris, inverse psoriasis, psoriaticarthritis, spondyloarthritis, epidermal inflammation, alopecia, alopeciaareata, rosacea, skin atrophy, steroid induced skin atrophy, photo skinageing, SAPHO syndrome, (synovitis, acne, pustulosis, hyperostosis andosteitis), acne vulgaris, hidradenitis suppurativa, urticaria, pruritis,and eczema.Clause 72. The method according to clause 71, wherein the dermaldisease, disorder or condition is inflammatory skin disorders.Clause 73. The method according to clause 71, wherein the dermaldisease, disorder or condition is dermatitis, atopic dermatitis,seborrheic dermatitis, contact dermatitis, including irritative contactdermatitis and allergic contact dermatitis or hand dermatitis.Clause 74. The method according to clause 73, wherein the dermaldisease, disorder or condition is atopic dermatitis.Clause 75. The method according to clause 71, wherein the dermaldisease, disorder or condition is psoriasis, psoriasis vulgaris, inversepsoriasis or psoriatic arthritis.Clause 76. The method according to clause 75, wherein the dermaldisease, disorder or condition is psoriasis.

1-17. (canceled)
 18. A compound which is5-(3-(4-fluorophenyl)azetidin-1-yl)-7-((tetrahydro-2H-pyran-4-yl)amino)-2,3-dihydrothieno[3,2-b]pyridine1-oxide having the formula:

or a pharmaceutically acceptable salt, enantiomer, or mixture ofenantiomers thereof.
 19. The compound according to claim 18, which is5-(3-(4-fluorophenyl)azetidin-1-yl)-7-((tetrahydro-2H-pyran-4-yl)amino)-2,3-dihydrothieno[3,2-b]pyridine1-oxide, or a pharmaceutically acceptable salt thereof.
 20. The compoundof claim 18, which is5-(3-(4-fluorophenyl)azetidin-1-yl)-7-((tetrahydro-2H-pyran-4-yl)amino)-2,3-dihydrothieno[3,2-b]pyridine1-oxide.
 21. A pharmaceutical composition comprising a compoundaccording to claim 18, or a pharmaceutically acceptable salt,enantiomer, mixture of enantiomers thereof, and a pharmaceuticallyacceptable excipient.
 22. The pharmaceutical composition according toclaim 21, wherein the pharmaceutical composition is in the form of anoral pharmaceutical composition.
 23. The pharmaceutical compositionaccording to claim 21, wherein the pharmaceutical composition is in theform of an oral sustained release or timed release pharmaceuticalcomposition.
 24. A method of treating or alleviating a disease, adisorder or a condition responsive to PDE4 inhibitory activity,comprising administering to a living animal body a therapeuticallyeffective amount of a compound according to claim
 18. 25. A method oftreating or ameliorating a dermal disease, disorder or condition,comprising administering to a person suffering from said disease,disorder or condition an effective amount of a compound according toaccording to claim
 18. 26. The method according to claim 25, wherein thedermal disease, disorder or condition is selected from the groupconsisting of a proliferative and inflammatory skin disorder,dermatitis, atopic dermatitis, seborrheic dermatitis, contactdermatitis, irritative contact dermatitis, allergic contact dermatitis,hand dermatitis, psoriasis, psoriasis vulgaris, inverse psoriasis,psoriatic arthritis, spondyloarthritis, epidermal inflammation,alopecia, alopecia areata, rosacea, skin atrophy, steroid induced skinatrophy, photo skin ageing, SAPHO syndrome, acne vulgaris, hidradenitissuppurativa, urticaria, pruritis, and eczema.
 27. The method accordingto claim 25, wherein the dermal disease, disorder or condition is atopicdermatitis.
 28. The method according to claim 25, wherein the dermaldisease, disorder or condition is psoriasis, psoriasis vulgaris, inversepsoriasis or psoriatic arthritis.
 29. A compound which is(1R)-5-(3-(4-fluorophenyl)azetidin-1-yl)-7-((tetrahydro-2H-pyran-4-yl)amino)-2,3-dihydrothieno[3,2-b]pyridine1-oxide having the formula:

or a pharmaceutically acceptable salt thereof.
 30. The compound of claim29, which is(1R)-5-(3-(4-fluorophenyl)azetidin-1-yl)-7-((tetrahydro-2H-pyran-4-yl)amino)-2,3-dihydrothieno[3,2-b]pyridine1-oxide.
 31. A pharmaceutical composition comprising a compoundaccording to claim 29, or a pharmaceutically acceptable salt,enantiomer, mixture of enantiomers thereof, and a pharmaceuticallyacceptable excipient.
 32. The pharmaceutical composition according toclaim 31, wherein the pharmaceutical composition is in the form of anoral pharmaceutical composition.
 33. The pharmaceutical compositionaccording to claim 31, wherein the pharmaceutical composition is in theform of an oral sustained release or timed release pharmaceuticalcomposition.
 34. A method of treating or alleviating a disease, adisorder or a condition responsive to PDE4 inhibitory activity,comprising administering to a living animal body a therapeuticallyeffective amount of a compound according to claim
 29. 35. A method oftreating or ameliorating a dermal disease, disorder or condition,comprising administering to a person suffering from said disease,disorder or condition an effective amount of a compound according toaccording to claim
 29. 36. The method according to claim 35, wherein thedermal disease, disorder or condition is selected from the groupconsisting of a proliferative and inflammatory skin disorder,dermatitis, atopic dermatitis, seborrheic dermatitis, contactdermatitis, irritative contact dermatitis, allergic contact dermatitis,hand dermatitis, psoriasis, psoriasis vulgaris, inverse psoriasis,psoriatic arthritis, spondyloarthritis, epidermal inflammation,alopecia, alopecia areata, rosacea, skin atrophy, steroid induced skinatrophy, photo skin ageing, SAPHO syndrome, acne vulgaris, hidradenitissuppurativa, urticaria, pruritis, and eczema.
 37. The method accordingto claim 35, wherein the dermal disease, disorder or condition is atopicdermatitis.
 38. The method according to claim 35, wherein the dermaldisease, disorder or condition is psoriasis, psoriasis vulgaris, inversepsoriasis or psoriatic arthritis.